The largest, most comprehensive genome-wide study of patients with inflammatory bowel disease (IBD)--including Crohn's disease and ulcerative colitis--has focused and narrowed the search for the genes that cause this common and debilitating illness, a team of researchers from the University of Chicago Medical Center, Johns Hopkins Medical Institutions, and the Marshfield Medical Research Foundation in Marshfield, Wisconsin report in the June 23, 1998 issue of the Proceedings of the National Academy of Scientists.

After typing 377 genetic markers on DNA from 439 IBD patients and 198 close relatives from 174 separate families, the researchers identified regions--on chromosomes 1p, 3q, and 4q--which appear to contain genes that trigger the onset of the disease.

They also confirmed the role of one previously localized gene named IBD1, near the center of chromosome 16, which appears to act in concert with the disease gene on chromosome 1.

"The prospect of finding the genes involved is exciting because we know so little about what causes IBD," said Judy Cho, MD, a gastroenterologist at the University of Chicago and lead author of the study. "This genetic approach is our best bet for unraveling the complicated set of events that initiates these disorders and developing more specific therapies to treat the disease and not just the symptoms."

Steven R. Brant, MD, director of the IBD Genetics Laboratory at Johns Hopkins and senior author of the study, said "Identifying the location of IBD genes is an important step toward the goal of preventing Crohn's disease and ulcerative colitis from occurring in genetically susceptible individuals." Brant is also an assistant professor of medicine.

Inflammatory bowel disease includes Crohn's disease (CD) and ulcerative colitis (UC)--chronic disorders that primarily affect the intestines, causing pain, severe diarrhea, intestinal bleeding, weight loss and fever. They afflict about 250 out of every 100,000 people, usually beginning in adolescents and young adults. Symptoms vary in severity and duration. Some patients suffer frequent prolonged attacks and others with fewer recurrences.

There is no cure for IBD. Treatments focus on controlling the inflammation through powerful drugs such as corticosteroids. Some patients require long-term use of medications, and many patients need surgery to remove inflamed or damaged portions of the intestines. Additional there is a greater risk of developing colorectal cancer.

Although environmental factors clearly contribute, these is strong evidence from studies of twins and affected families that IBD--especially Crohn's disease--has a genetic basis. The patterns of inheritance, however, are extremely complex. Multiple genes play a role--some affecting CD, some UC, and some both.

IBD is two to eight times more common in Ashkenazi Jews. This is the first genome-wide study to look at Ashkenazi Jews, who made up 37 percent of the families in this study.

The complex inheritance patterns were reflected by this study's results. The researchers looked at families with either CD, UC, or both. They found a strong link between a gene on chromosome 1 for all families, but most of the evidence for this association came from families who were not of Ashkenazi Jewish heritage.

The linkage on chromosome 3q involved all families. But the association between the region on chromosome 4 was stronger for families that have both CD and UC, especially for those of Ashkenazi Jewish heritage.

"Although we now have some great clues, we are years away from isolating the individual genes that contribute to this disease," said Cho. Each suspect region contains hundreds of genes. "Once we narrow the search we still have to find out how these genes interact with the environment and each other. But it's still a tremendous boost to move one big step further toward unraveling this baffling disease and starting to develop better treatments."

Support for the research was provided by: the Crohn's and Colitis Foundation of America; the Gastrointestinal Research Foundation; the Logan Center for Gastrointestinal Research, University of Chicago; the Myerhoff Inflammatory Bowel Disease Center, Hopkins; the Mazza Foundation; the Edison Foundation; Glaxo Institute for Digestive Health; and the National Institutes of Health.

Summary:
The largest, most comprehensive genome-wide study of patients with inflammatory bowel disease, including Crohn's disease and ulcerative colitis, has narrowed the search for the genes that cause this common and debilitating illness--identifying new regions on chromosomes 1p, 3q, and 4q that may contain genes that trigger IBD.